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Biomedical subjects

H Nguyen

Publications and source records attributed to H Nguyen.

At least 19 recordsLinked to original sources
PubMed1999

Nitric oxide and thromboxane A2-mediated pulmonary microvascular dysfunction.

OBJECTIVES: To examine whether the lung releases nitric oxide (NO) in response to thromboxane A2 and to examine the local release of NO as a protective compensatory mechanism by which the lung responds to the proinflammatory and vasoactive effects of thromboxane A2. DESIGN: The lungs of anesthetized Sprague-Dawley rats were perfused in vitro with Krebs-Henseleit buffer that contained an inhibitor of NO synthase (nitroglycerinenitro-L-arginine methyl ester [L-NAME]) (10(-4) mol/L), an NO donor (sodium nitroprusside) (10(-8) mol/L), or perfusate alone. Following equilibration, the thromboxane A2 receptor agonist 9,11-dideoxy-11alpha, 9alpha-epoxymethanoprostaglandin F2alpha(U-46619) (7.1 X 10(-8) mol/L) was added to the perfusate. Fifteen minutes later, the capillary filtration coefficient, pulmonary arterial pressure, and vascular resistance were measured. Pulmonary NO release was assessed by quantitating the release of cyclic guanosine monophosphate into the perfusate. RESULTS: The capillary filtration coefficient of lungs exposed to U-46619 was 3.5 times greater than that of lungs perfused with buffer alone (P<.05). The addition of sodium nitroprusside reduced the increase in capillary filtration coefficient associated with U-46619 by 50% (P<.05) whereas L-NAME had no effect. The addition of U-46619 to the perfused lung caused a 3.0+/-0.4 mm Hg increase in pulmonary artery pressure (P<.01) with a corresponding rise in total vascular resistance (P<.05). This effect was exacerbated by L-NAME (P<.05) and inhibited by sodium nitroprusside (P<.05). Exposure of the isolated lungs to U-46619 caused a 4-fold increase in cyclic guanosine monophosphate levels within the perfusate. CONCLUSION: These data are consistent with the hypothesis that NO release may be an important protective mechanism by which the lung responds to thromboxane A2.

Animals↗
PubMed1999

Effect of interleukin-6 secreted by engineered human stromal cells on osteoclasts in human bone.

The effect of elevated human IL-6 (hIL-6) production by human bone marrow (Hu-BM) stromal cells on osteoclasts in human bone was examined. Human bone was implanted into nonobese diabetic mice with severe combined immunodeficiency (Hu-Bone-NOD/SCID mice). Immunohistochemistry of bone implants and mouse spleens (at 20 weeks), showed human CD45+ cells, B cells, and macrophages in both tissues. Thus, Hu-BM cells survive human bone transplantation and infiltrate mouse tissue. Bone implants had 75 +/- 12% (mean +/- SD) human CD45+ cells, and 9 +/- 4% mouse hematopoietic cells. A retrovirus vector containing the human IL-6 gene was used to transduce Hu-BM stromal cells (IL-6/stromal) and the PA317 cell line (IL-6/PA317). IL-6/ stromal cells (secreting, on average, 17 microg of hIL-6/10(6) cells per 24 h) were injected directly into human bone implants in Hu-Bone-NOD/SCID mice. IL-6/PA317 cells (secreting 16 microg/mL of hIL-6/10(6) cells per 24 h) were injected intraperitoneally into Hu-Bone-NOD/SCID mice. Analyses of sera from both groups of animals showed elevated levels of IL-6. However, only bone implants engrafted with IL-6/stromal cells had a statistically significant increase in osteoclast-lined mineralized trabecular bone surface (BS). Thus, a high concentration of serum hIL-6 in Hu-Bone-NOD/SCID mice alone does not increase osteoclast-lined BS in bone implants. Most importantly, it is the type of human BM cell that secretes the high levels of hIL-6 that is most critical.

Animals↗
PubMed1999

Calcium influx through NMDA receptors, chronic receptor inhibition by ethanol and 2-amino-5-phosponopentanoic acid, and receptor protein expression.

Chronic treatment of neurons with either ethanol or competitive and noncompetitive antagonists of NMDA receptors leads to enhanced expression of NMDA receptor density and function in neurons. The signal transduction pathways for such receptor up-regulation are not known. The focus of the present study was on the role of Ca2+ entry into neurons, either through receptor or voltage-gated channels, in the expression of the NMDA receptor subunit NR1 and the 71-kDa glutamate-binding protein (GBP) of a glutamate/NMDA receptor-like complex. Chronic inhibition of NMDA receptors in cortical neurons in primary cultures by either 100 mM ethanol or 100 microM 2-amino-5-phosphonopentanoic acid (2-AP5) increased the expression of NR1 and GBP. The effect of 2-AP5 on the expression of the two proteins was not additive with that of ethanol when neuronal cultures were treated with both agents at the same time. However, the effects of ethanol on NR1 and GBP expression were blocked by the simultaneous treatment with NMDA (50 microM). Activation or inhibition of other glutamate ionotropic receptors had no effect on the expression of NR1 and GBP. The inhibition of L- or N-type voltage-sensitive Ca2+ channels and voltage-gated Na+ channels also had little effect on the expression of either protein; neither did exposure of neurons to elevated extracellular Ca2+ concentrations (3 or 5 mM). On the other hand, treatment of neurons for 48 h with the intracellular Ca2+ chelator BAPTA-AM as well as partial chelation of extracellular Ca2+ with EGTA caused an up-regulation in NR1 and GBP expression. The enhanced expression of NR1 in neurons treated for 48 h with either ethanol or EGTA was correlated with increases in the activity of NMDA receptors demonstrated as a doubling of the NMDA-stimulated rise in intracellular free Ca2+ concentration. The effects of chronic administration of EGTA on both NR1 expression as well as NMDA receptor function were probably related to an acute inhibition by EGTA of NMDA-induced Ca2+ influx into neurons. It appears that the expression of both the NR1 subunit of NMDA receptors and the GBP of a receptor-like complex is regulated by intracellular Ca2+, especially that entering through NMDA receptor ion channels.

2-Amino-5-phosphonovalerate↗
PubMed1999

Triggering the interferon response: the role of IRF-3 transcription factor.

The interferon (IFN) regulatory factors (IRF) consist of a growing family of related transcription proteins first identified as regulators of the IFN-alpha/beta gene promoters, as well as the IFN-stimulated response element (ISRE) of some IFN-stimulated genes. IRF-3 was originally identified as a member of the IRF family based on homology with other IRF family members and on binding to the ISRE of the IFN-stimulated gene 15 (ISG15) promoter. Several recent studies have focused attention on the unique molecular properties of IRF-3 and its role in the regulation of IFN gene expression. IRF-3 is expressed constitutively in a variety of tissues, and the relative levels of IRF-3 mRNA do not change in virus-infected or IFN-treated cells. Following virus infection, IRF-3 is posttranslationally modified by protein phosphorylation at multiple serine and threonine residues, located in the carboxy-terminus of IRF-3. Phosphorylation causes the cytoplasmic to nuclear translocation of IRF-3, stimulation of DNA binding, and increased transcriptional activation, mediated through the association of IRF-3 with the CBP/p300 coactivator. The purpose of this review is to summarize recent investigations demonstrating the important role of IRF-3 in cytokine gene transcription. These studies provide the framework for a model in which virus-dependent phosphorylation of IRF-3 alters protein conformation to permit nuclear translocation, association with transcriptional partners, and primary activation of IFN and IFN-responsive genes.

Amino Acid Sequence↗
PubMed1999

Mycobacterium species identification and rifampin resistance testing with high-density DNA probe arrays.

Species identification within the genus Mycobacterium and subsequent antibiotic susceptibility testing still rely on time-consuming, culture-based methods. Despite the recent development of DNA probes, which greatly reduce assay time, there is a need for a single platform assay capable of answering the multitude of diagnostic questions associated with this genus. We describe the use of a DNA probe array based on two sequence databases: one for the species identification of mycobacteria (82 unique 16S rRNA sequences corresponding to 54 phenotypical species) and the other for detecting Mycobacterium tuberculosis rifampin resistance (rpoB alleles). Species identification or rifampin resistance was determined by hybridizing fluorescently labeled, amplified genetic material generated from bacterial colonies to the array. Seventy mycobacterial isolates from 27 different species and 15 rifampin-resistant M. tuberculosis strains were tested. A total of 26 of 27 species were correctly identified as well as all of the rpoB mutants. This parallel testing format opens new perspectives in terms of patient management for bacterial diseases by allowing a number of genetic tests to be simultaneously run.

Antibiotics, Antitubercular↗
PubMed1999

IkappaB-mediated inhibition of virus-induced beta interferon transcription.

We have examined the consequences of overexpression of the IkappaBalpha and IkappaBbeta inhibitory proteins on the regulation of NF-kappaB-dependent beta interferon (IFN-beta) gene transcription in human cells after Sendai virus infection. In transient coexpression studies or in cell lines engineered to express different forms of IkappaB under tetracycline-inducible control, the IFN-beta promoter (-281 to +19) linked to the chloramphenicol acetyltransferase reporter gene was differentially inhibited in response to virus infection. IkappaBalpha exhibited a strong inhibitory effect on virus-induced IFN-beta expression, whereas IkappaBbeta exerted an inhibitory effect only at a high concentration. Despite activation of the IkappaB kinase complex by Sendai virus infection, overexpression of the double-point-mutated (S32A/S36A) dominant repressors of IkappaBalpha (TD-IkappaBalpha) completely blocked IFN-beta gene activation by Sendai virus. Endogenous IFN-beta RNA production was also inhibited in Tet-inducible TD-IkappaBalpha-expressing cells. Inhibition of IFN-beta expression directly correlated with a reduction in the binding of NF-kappaB (p50-RelA) complex to PRDII after Sendai virus infection in IkappaBalpha-expressing cells, whereas IFN-beta expression and NF-kappaB binding were only slightly reduced in IkappaBbeta-expressing cells. These experiments demonstrate a major role for IkappaBalpha in the regulation of NF-kappaB-induced IFN-beta gene activation and a minor role for IkappaBbeta in the activation process.

Amino Acid Sequence↗
PubMed1999

Cell-free degradation of p27(kip1), a G1 cyclin-dependent kinase inhibitor, is dependent on CDK2 activity and the proteasome.

Entry into S phase is dependent on the coordinated activation of CDK4,6 and CDK2 kinases. Once a cell commits to S phase, there must be a mechanism to ensure the irreversibility of this decision. The activity of these kinases is inhibited by their association with p27. In many cells, p27 plays a major role in the withdrawal from the cell cycle in response to environmental cues. Thus, it is likely that p27 is a target of the machinery required to ensure the irreversibility of S-phase entry. We have been interested in understanding the mechanisms regulating p27 at the G1/S transition. In this report, we define a cell-free degradation system which faithfully recapitulates the cell cycle phase-specific degradation of p27. We show that this reaction is dependent on active CDK2 activity, suggesting that CDK2 activity is directly required for p27 degradation. In addition to CDK2, other S-phase-specific factors are required for p27 degradation. At least some of these factors are ubiquitin and proteasome dependent. We discuss the relationships between CDK2 activity, ubiquitin-dependent, and possibly ubiquitin-independent proteasomal activities in S-phase extracts as related to p27.

Base Sequence↗
PubMed1999

Ethanol modulation of intestinal epithelial tight junction barrier.

Previous studies have shown that high concentrations of ethanol (>/=40%) cause functional damage of the gastrointestinal epithelial barrier by direct cytotoxic effect on the epithelial cells. The effects of lower noncytotoxic doses of ethanol on epithelial barrier function are unknown. A major function of gastrointestinal epithelial cells is to provide a barrier against the hostile substances in the gastrointestinal lumen. The apicolaterally located tight junctions (TJs) form a paracellular seal between the lateral membranes of adjacent cells and act as a paracellular barrier. In this study, we investigated the effects of lower doses of ethanol on intestinal epithelial TJ barrier function using filter-grown Caco-2 intestinal epithelial monolayers. The Caco-2 TJ barrier function was assessed by measuring epithelial resistance or paracellular permeability of the filter-grown monolayers. Ethanol (0, 1, 2.5, 5, 7.5, and 10%) produced a dose-related drop in Caco-2 epithelial resistance and increase in paracellular permeability. Ethanol also produced a progressive disruption of TJ protein (ZO-1) with separation of ZO-1 proteins from the cellular junctions and formation of large gaps between the adjacent cells. Ethanol, at the doses used (</=10%), did not cause cytotoxicity (lactate dehydrogenase release) to the Caco-2 cells. Ethanol produced a disassembly and displacement of perijunctional actin and myosin filaments from the perijunctional areas. On ethanol removal, actin and myosin filaments rapidly reassembled at the cellular borders. Ethanol stimulated the Caco-2 myosin light chain kinase (MLCK) activity but did not affect the MLCK protein levels. Specific MLCK inhibitor ML-7 inhibited both ethanol increases in MLCK activity and TJ permeability without affecting the MLCK protein levels. Consistent with these findings, metabolic inhibitors sodium azide and 2,4-dinitrophenol significantly prevented ethanol-induced increase in Caco-2 TJ permeability, whereas cycloheximide or actinomycin D had no effect. The results of this study indicate that ethanol at low noncytotoxic doses causes a functional and structural opening of the Caco-2 intestinal epithelial TJ barrier by activating MLCK.

Azepines↗
PubMed1999

NGF activates similar intracellular signaling pathways in vascular smooth muscle cells as PDGF-BB but elicits different biological responses.

The signaling pathways that regulate smooth muscle cell migration and proliferation are incompletely understood. Smooth muscle cells express at least 3 families of receptor tyrosine kinases that mediate cell migration: platelet-derived growth factor (PDGF) receptors, the trk family of neurotrophin receptors, and insulin-like growth factor 1 receptor. The neurotrophin, nerve growth factor (NGF), and insulin-like growth factor 1 induce the migration but not the proliferation of smooth muscle cells, whereas PDGF-BB stimulates both responses. To determine whether distinct signaling pathways downstream of receptor tyrosine kinases specifically mediate smooth muscle cell migration or proliferation, the ligand-induced activation of different signaling pathways in smooth muscle cells was examined. NGF induces prolonged activation of the Shc/MAP kinase pathway and phospholipase Cgamma compared with PDGF-BB. The activation of phosphatidylinositol-3 kinase, however, was 10-fold greater in response to PDGF-BB compared with NGF. Insulin-like growth factor 1 activates only phosphatidylinositol-3 kinase. Pharmacological inhibitors of phosphatidylinositol-3 kinase, Wortmannin and LY294002, inhibit PDGF-BB and NGF-induced migration, whereas an inhibitor of MAP kinase kinase, PD98059, has no effect. Our results suggest that (1) different receptor tyrosine kinases use similar patterns of activation of signaling pathways to mediate distinct biological outcomes of cell migration and proliferation, (2) NGF activates signaling proteins in smooth muscle cells similar to those activated during NGF-induced neuronal differentiation, and (3) the combinatorial effects of different signaling pathways are important for the regulation of smooth muscle cell migration and proliferation. Further studies using mutant trk receptors will help to define the signal transduction pathways mediating NGF-induced smooth muscle cell migration.

Animals↗
PubMed1999

Arterial baroreflex control of the sinus node during dobutamine exercise stress testing.

The contributions of increases in circulating catecholamines, changes in central command, and muscle afferents on baroreflex control of the sinus node during exercise are unclear. We used a dobutamine infusion to induce hemodynamic changes comparable to those of moderate physical exercise in the absence of changes in central command and muscle afferents in 13 healthy subjects. Dobutamine (up to 9 microg/kg body weight per minute) increased systolic blood pressure, shortened the RR interval, increased systolic blood pressure variability, but blunted RR interval variability (P<0.05 versus placebo). Consequently, dobutamine decreased the coherence between variations in systolic blood pressure and RR interval and decreased arterial baroreflex sensitivity from 12+/-2 to 3+/-1 ms/mm Hg (P<0.01). The largest increases in systolic blood pressure with dobutamine were paralleled by the greatest impairments in arterial baroreflex sensitivity (0. 50<r<0.56, P<0.01). The chronotropic effects of dobutamine prevented a reflex bradycardia in response to the blood pressure increase. However, less predominant low-frequency oscillations in systolic blood pressure (P<0.0001) suggested preserved sympathetic withdrawal in response to the blood pressure increase induced by dobutamine. In conclusion, this study revealed that a shift in the operating point of the arterial baroreceptors and the chronotropic effects of adrenergic stimulation impair baroreflex control of the sinus node during dobutamine exercise stress testing. Baroreflex control of the sinus node is not reset when hemodynamic characteristics of exercise are reproduced in the absence of modifications in central command and muscles afferents.

Adult↗
PubMed1999

Lengthening of the Achilles tendon in diabetic patients who are at high risk for ulceration of the foot.

BACKGROUND: The purpose of this study was to determine the degree to which pressure on the plantar aspect of the forefoot is reduced following percutaneous lengthening of the Achilles tendon in diabetic patients who are at high risk for ulceration of the foot. METHODS: Ten diabetic patients who had a history of neuropathic plantar ulceration of the forefoot were enrolled in a laboratory gait trial. A repeated-measures design and a computer analysis of force-plate data were used to examine dynamic pressures on the forefoot, with the patient walking barefoot, immediately before percutaneous lengthening of the Achilles tendon and at eight weeks afterward. Although the wound in each patient had healed at least one month before the operation, we considered the patients to be at high risk for ulceration because they had had an ulcer previously. RESULTS: The mean peak pressure (and standard deviation) on the plantar aspect of the forefoot decreased significantly from 86+/-9.4 newtons per square centimeter preoperatively to 63+/-13.2 newtons per square centimeter at eight weeks postoperatively (p<0.001). Commensurately, the mean dorsiflexion of the ankle joint increased significantly from 0+/-3.1 degrees preoperatively to 9+/-2.3 degrees at eight weeks post-operatively (p<0.001). CONCLUSIONS: The results of this study suggest that peak pressures on the plantar aspect of the forefoot are significantly reduced following percutaneous lengthening of the Achilles tendon in diabetic patients who are at high risk for ulceration of the foot. We are unaware of any other reports in the medical literature that describe such findings. These data may lend support to studies that have indicated that this procedure should be used as an adjunctive therapeutic or prophylactic measure to reduce the risk of neuropathic ulceration.

Achilles Tendon↗
PubMed1998

Varicella-zoster virus ORF61 deletion mutants replicate in cell culture, but a mutant with stop codons in ORF61 reverts to wild-type virus.

Varicella-zoster virus (VZV) ORF61 encodes a phosphoprotein that transactivates VZV promoters. Transfection of cells with cosmid DNAs, including a cosmid with a large deletion in ORF61, resulted in a VZV ORF61 deletion mutant that was impaired for growth in vitro and could be partially complemented by growth in neuroblastoma or osteosarcoma cell lines. Cells infected with the VZV ORF61 deletion mutant expressed normal levels of an immediate-early VZV protein, but had reduced levels of a late protein and showed abnormal syncytia. Carboxy terminal truncation mutants of VZV ORF61 protein have a transrepressing phenotype and inhibit the infectivity of cotransfected wild-type viral DNA. Transfection of cells with cosmid DNAs, including a cosmid with stop codons that should result in an ORF61 truncation mutant expressing a transrepressing protein that retains the RING finger domain, resulted in a viral genome which reverted back to the wild-type sequence. BAL-31 exonuclease was used to produce deletions at the site of the stop codons in ORF61 of the cosmid, resulting in loss of the RING finger domain. Transfection of tissue culture cells with the ORF61 BAL-31 deletion mutants and other cosmid DNAs yielded viable viruses. Thus, while deletion mutants lacking the RING finger domain of ORF61 replicate in cell culture, a mutant with stop codons that retains this domain could not be propagated and reverted to wild-type virus.

Codon, Terminator↗
PubMed1998

Hormone-dependent coactivator binding to a hydrophobic cleft on nuclear receptors.

The ligand-binding domain of nuclear receptors contains a transcriptional activation function (AF-2) that mediates hormone-dependent binding of coactivator proteins. Scanning surface mutagenesis on the human thyroid hormone receptor was performed to define the site that binds the coactivators, glucocorticoid receptor-interacting protein 1 (GRIP1) and steroid receptor coactivator 1 (SRC-1). The residues involved encircle a small surface that contains a hydrophobic cleft. Ligand activation of transcription involves formation of this surface by folding the carboxyl-terminal alpha helix against a scaffold of three other helices. These features may represent general ones for nuclear receptors.

HeLa Cells↗
PubMed1998

Montelukast for chronic asthma in 6- to 14-year-old children: a randomized, double-blind trial. Pediatric Montelukast Study Group.

CONTEXT: Leukotrienes are important mediators of asthma by causing bronchoconstriction, mucous secretion, and increased vascular permeability. Studies using compounds that block leukotrienes have demonstrated improvement in asthma control in adults and adolescents, but children younger than 12 years, for whom asthma is the most common chronic disease, have not been studied. OBJECTIVE: To determine the clinical effect of montelukast, a leukotriene receptor antagonist, in 6- to 14-year-old children with asthma. DESIGN: Eight-week, multicenter, randomized, double-blind study. SETTING: Forty-seven outpatient centers at private practices and academic medical centers in the United States and Canada. PATIENTS: A total of 336 children with forced expiratory volume in 1 second (FEV1) between 50% to 85% of the predicted value, at least 15% reversibility after inhaled beta-agonist administration, a minimal predefined level of daytime asthma symptoms, and daily beta-agonist use. Concomitant inhaled corticosteroids at a constant daily dose were used by 39% of patients receiving montelukast and 33% receiving placebo. INTERVENTION: After a 2-week placebo run-in period, patients received either montelukast (5-mg chewable tablet) or matching-image placebo once daily at bed-time for 8 weeks. MAIN OUTCOME MEASURE: Morning FEV1 percent change from baseline. RESULTS: Mean morning FEV1 increased from 1.85 L to 2.01 L in the montelukast group and from 1.85 L to 1.93 L in the placebo group. This represents an 8.23% (95% confidence interval [CI], 6.33% to 10.13%) increase from baseline in the montelukast group and a 3.58% (95% CI, 1.29% to 5.87%) increase from baseline in the placebo group (P<.001 for montelukast vs placebo). CONCLUSION: Montelukast improves morning FEV1 in 6- to 14-year-old children with chronic asthma.

Acetates↗
PubMed1998

A transgenic myogenic cell line lacking ryanodine receptor protein for homologous expression studies: reconstitution of Ry1R protein and function.

CCS embryonic stem (ES) cells possessing two mutant alleles (ry1r-/ry1r-) for the skeletal muscle ryanodine receptor (RyR) have been produced and injected subcutaneously into severely compromised immunodeficient mice to produce teratocarcinomas in which Ry1R expression is absent. Several primary fibroblast cell lines were isolated and subcloned from one of these tumors that contain the knockout mutation in both alleles and exhibit a doubling time of 18-24 h, are not contact growth inhibited, do not exhibit drastic morphological change upon serum reduction, and possess the normal complement of chromosomes. Four of these fibroblast clones were infected with a retrovirus containing the cDNA encoding myoD and a puromycin selection marker. Several (1-2 microg/ml) puromycin-resistant subclones from each initial cell line were expanded and examined for their ability to express myoD and to form multinucleated myotubes that express desmin and myosin upon removal of mitogens. One of these clones (1B5 cells) was selected on this basis for further study. These cells, upon withdrawal of mitogens for 5-7 d, were shown by Western blot analysis to express key triadic proteins, including skeletal triadin, calsequestrin, FK506-binding protein, 12 kD, sarco(endo)plasmic reticulum calcium-ATPase1, and dihydropyridine receptors. Neither RyR isoform protein, Ry1R (skeletal), Ry2R (cardiac), nor Ry3R (brain), were detected in differentiated 1B5 cells. Measurements of intracellular Ca2+ by ratio fluorescence imaging of fura-2-loaded cells revealed that differentiated 1B5 cells exhibited no responses to K+ (40 mM) depolarization, ryanodine (50-500 microM), or caffeine (20-100 mM). Transient transfection of the 1B5 cells with the full-length rabbit Ry1R cDNA restored the expected responses to K+ depolarization, caffeine, and ryanodine. Depolarization-induced Ca2+ release was independent of extracellular Ca2+, consistent with skeletal-type excitation-contraction coupling. Wild-type Ry1R expressed in 1B5 cells were reconstituted into bilayer lipid membranes and found to be indistinguishable from channels reconstituted from rabbit sarcoplasmic reticulum with respect to unitary conductance, open dwell times, and responses to ryanodine and ruthenium red. The 1B5 cell line provides a powerful and easily managed homologous expression system in which to study how Ry1R structure relates to function.

Animals↗
PubMed1998

In vivo knee joint loading and kinematics before and after ACL transection in an animal model.

Osteoarthritis (OA) is typically diagnosed in humans in its final stage when joint movement becomes painful. Clinical information about the onset and the mechanisms triggering the degenerative responses are virtually non-existent. However, research on animal models of experimental OA shows that joint adaptations associated with the onset of OA can be detected as early as two to four weeks following disruption of the normal joint mechanics. Transection of the anterior cruciate ligament (ACL) has been shown to cause OA-like symptoms in various animal models including the cat. However. the changes in joint loading responsible for the early tissue responses have not been quantified in vivo. Consequently, the relationship between abnormal joint loading and the onset of OA remains unknown. The purpose of this study was to quantify knee loading before and early after ACL transection in the cat. Knee mechanics were assessed by measuring patellar tendon forces, gastrocnemius forces, knee flexor and extensor EMGs, and hindlimb kinematics before and 5, 7, and 9 days following ACL transection in six experimental and two sham-operated animals. The knee mechanics were not affected by sham-surgery but the muscular forces. knee extensor EMGs, and knee range of motion were reduced following ACL transection compared to corresponding pre-intervention values. These results suggest that ACL transection causes a general unloading and changed kinematics of the knee. We speculate that the decrease in loading and the altered kinematics are responsible for the onset of biologic adaptations of the knee. Precise data about the local joint contact mechanics before and after ACL transection are now required to further relate the detailed changes in the knee mechanics to the early joint changes.

Animals↗